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1.  Molecular characterization and copy number of SMN1, SMN2 and NAIP in Chinese patients with spinal muscular atrophy and unrelated healthy controls 
Spinal muscular atrophy (SMA) is caused by SMN1 dysfunction, and the copy number of SMN2 and NAIP can modify the phenotype of SMA. The aim of this study was to analyze the copy numbers and gene structures of SMA-related genes in Chinese SMA patients and unrelated healthy controls.
Forty-two Chinese SMA patients and two hundred and twelve unrelated healthy Chinese individuals were enrolled in our study. The copy numbers and gene structures of SMA-related genes were measured by MLPA assay.
We identified a homozygous deletion of SMN1 in exons 7 and 8 in 37 of 42 patients (88.1%); the other 5 SMA patients (11.9%) had a single copy of SMN1 exon 8. The proportions of the 212 unrelated healthy controls with different copy numbers for the normal SMN1 gene were 1 copy in 4 individuals (1.9%), 2 copies in 203 (95.7%) and 3 copies in 5 (2.4%). Three hybrid SMN genes and five genes that lack partial sequences were found in SMA patients and healthy controls. Distributions of copy numbers for normal SMN2 and NAIP were significantly different (P < 0.001) in people with and without SMA.
The copy numbers and gene structures of SMA-related genes were different in Chinese SMA patients and healthy controls.
PMCID: PMC4328246
Chinese; MLPA; SMA; Gene copy number
2.  Identification of genetic variants or genes that are associated with Homoharringtonine (HHT) response through a genome-wide association study in human lymphoblastoid cell lines (LCLs) 
Frontiers in Genetics  2015;5:465.
Homoharringtonine (HHT) has been widely used in China to treat patients with acute and chronic myeloid leukemia for decades. Since response to HHT varies among patients, our study aimed to identify biomarkers that might influence the response to HHT using a panel of various human lymphoblastoid cell lines (LCLs). Genome-wide association (GWA) analysis using single nucleotide polymorphism (SNP) and mRNA expression data was assessed for association with cytotoxicity to HHT in LCLs. Integrated analysis among SNPs, expression, AUC value was also performed to help select candidate genes for further functional characterization. Functional validation of candidate genes was performed using leukemia cell lines (U937, K562). Candidate genes were knocked down using specific siRNA and its response to HHT was assessed using MTS assay. We found that 15 expression probes were associated with HHT AUC with P < 10−4, and 96 individual probe sets with P < 10−3. Eighteen SNPs were associated with HHT AUC with P < 10−5 and 281 SNPs with P < 10−4. The integrated analysis identified 4 unique SNPs that were associated with both expression and AUC. Functional validation using siRNA knockdown in leukemia cell lines showed that knocking down CCDC88A, CTBP2, SOCS4 genes in U937 and K562 cells significantly altered HHT cytotoxicity. In summary, this study performed with LCLs can help to identify novel biomarker that might contribute to variation in response to HHT therapy.
PMCID: PMC4292778  PMID: 25628645
genome-wide association study; biomarkers; Homoharringtonine (HHT); lymphoblastoid cell line system; leukemia
3.  Tacrolimus in preventing transplant rejection in Chinese patients – optimizing use 
Tacrolimus is a product of fermentation of Streptomyces, and belongs to the family of calcineurin inhibitors. It is a widely used immunosuppressive drug for preventing solid-organ transplant rejection. Compared to cyclosporine, tacrolimus has greater immunosuppressive potency and a lower incidence of side effects. It has been accepted as first-line treatment after liver and kidney transplantation. Tacrolimus has specific features in Chinese transplant patients; its in vivo pharmacokinetics, treatment regimen, dose and administration, and adverse-effect profile are influenced by multiple factors, such as genetics and the spectrum of primary diseases in the Chinese population. We reviewed the clinical experience of tacrolimus use in Chinese liver- and kidney-transplant patients, including the pharmacology of tacrolimus, the immunosuppressive effects of tacrolimus versus cyclosporine, effects of different factors on tacrolimus metabolism on Chinese patients, personalized medicine, clinical safety profile, and patient satisfaction and adherence. This article provides guidance for the rational and efficient use of tacrolimus in Chinese organ-transplant patients.
PMCID: PMC4298305  PMID: 25609922
tacrolimus; liver transplantation; kidney transplant; Chinese; personalized medicine
4.  Expression of turtle riboflavin-binding protein represses mitochondrial electron transport gene expression and promotes flowering in Arabidopsis 
BMC Plant Biology  2014;14(1):381.
Recently we showed that de novo expression of a turtle riboflavin-binding protein (RfBP) in transgenic Arabidopsis increased H2O2 concentrations inside leaf cells, enhanced the expression of floral regulatory gene FD and floral meristem identity gene AP1 at the shoot apex, and induced early flowering. Here we report that RfBP-induced H2O2 presumably results from electron leakage at the mitochondrial electron transport chain (METC) and this source of H2O2 contributes to the early flowering phenotype.
While enhanced expression of FD and AP1 at the shoot apex was correlated with early flowering, the foliar expression of 13 of 19 METC genes was repressed in RfBP-expressing (RfBP+) plants. Inside RfBP+ leaf cells, cytosolic H2O2 concentrations were increased possibly through electron leakage because similar responses were also induced by a known inducer of electron leakage from METC. Early flowering no longer occurred when the repression on METC genes was eliminated by RfBP gene silencing, which restored RfBP+ to wild type in levels of FD and AP1 expression, H2O2, and flavins. Flowering was delayed by the external riboflavin application, which brought gene expression and flavins back to the steady-state levels but only caused 55% reduction of H2O2 concentrations in RfBP+ plants. RfBP-repressed METC gene expression remedied the cytosolic H2O2 diminution by genetic disruption of transcription factor NFXLl and compensated for compromises in FD and AP1 expression and flowering time. By contrast, RfBP resembled a peroxisomal catalase mutation, which augments the cytosolic H2O2, to enhance FD and AP1 expression and induce early flowering.
RfBP-repressed METC gene expression potentially causes electron leakage as one of cellular sources for the generation of H2O2 with the promoting effect on flowering. The repressive effect on METC gene expression is not the only way by which RfBP induces H2O2 and currently unappreciated factors may also function under RfBP+ background.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-014-0381-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4310184  PMID: 25547226
5.  Liriodenine induces the apoptosis of human laryngocarcinoma cells via the upregulation of p53 expression 
Oncology Letters  2014;9(3):1121-1127.
Laryngocarcinoma is one of the most aggressive cancers that affects the head and neck region. The survival rate of patients with laryngocarcinoma is low due to late metastases and the resistance of the disease to chemotherapy and radiotherapy. Liriodenine, an alkaloid extracted from a number of plant species, has demonstrated antitumor effects on multiple types of cancer. However, the effects of liriodenine upon laryngocarcinoma, and the underlying mechanisms, are yet to be elucidated. The present study therefore investigated the potential antitumor effects of liriodenine on HEp-2 human laryngocarcinoma cells in vitro and HEp-2-implanted nude mice in vivo. Liriodenine induced significant apoptosis and inhibition of cell migration in the HEp-2 cells. Furthermore, the rate of tumor growth in the HEp-2-implanted nude mice was inhibited by the administration of liriodenine. The potential mechanism underlying the antitumor effects of liriodenine may result from an upregulative effect upon p53 expression, which ultimately induces cellular apoptosis. By contrast, the downregulation of p53 significantly reduced the antitumor effects of liriodenine. Together, these results suggest that liriodenine exhibits potent antitumor activities in laryngocarcinoma HEp-2 cells, in vitro and in vivo, via the upregulation of p53 expression. Liriodenine may therefore be a potential therapy for the treatment of laryngocarcinoma.
PMCID: PMC4314988  PMID: 25663867
laryngocarcinoma; liriodenine; p53; HEp-2 cells; nude mice
6.  Acupuncture at heterotopic acupoints enhances jejunal motility in constipated and diarrheic rats 
World Journal of Gastroenterology : WJG  2014;20(48):18271-18283.
AIM: To investigate the effect and mechanism of acupuncture at heterotopic acupoints on jejunal motility, particularly in pathological conditions.
METHODS: Jejunal motility was assessed using a manometric balloon placed in the jejunum approximately 18-20 cm downstream from the pylorus and filled with approximately 0.1 mL warm water in anesthetized normal rats or rats with diarrhea or constipation. The heterotopic acupoints including LI11 (Quchi), ST37 (Shangjuxu), BL25 (Dachangshu), and the homotopic acupoint ST25 (Tianshu), and were stimulated for 60 s by rotating acupuncture needles right and left at a frequency of 2 Hz. To determine the type of afferent fibers mediating the regulation of jejunal motility by manual acupuncture, the ipsilateral sciatic A or C fibers of ST37 were inactivated by local application of the A-fiber selective demyelination agent cobra venom or the C fiber blocker capsaicin. Methoctramine, a selective M2 receptor antagonist, was injected intravenously to identify a specific role for M2 receptors in mediating the effect of acupuncture on jejunal motility.
RESULTS: Acupuncture at heterotopic acupoints, such as LI11 and ST37, increased jejunal motility not only in normal rats, but also in rats with constipation or diarrhea. In normal rats, manual acupuncture at LI11 or ST37 enhanced jejunal pressure from 7.34 ± 0.19 cmH2O to 7.93 ± 0.20 cmH2O, an increase of 9.05% ± 0.82% (P < 0.05), and from 6.95 ± 0.14 cmH2O to 8.97 ± 0.22 cmH2O, a significant increase of 27.44% ± 1.96% (P < 0.01), respectively. In constipated rats, manual acupuncture at LI11 or ST37 increased intrajejunal pressure from 8.17 ± 0.31 cmH2O to 9.86 ± 0.36 cmH2O, an increase of 20.69% ± 2.10% (P < 0.05), and from 8.82 ± 0.28 cmH2O to 10.83 ± 0.28 cmH2O, an increase of 22.81% ± 1.46% (P < 0.05), respectively. In rats with diarrhea, MA at LI11 or ST37 increased intrajejunal pressure from 11.95 ± 0.35 cmH2O to 13.96 ± 0.39 cmH2O, an increase of 16.82% ± 2.35% (P < 0.05), and tended to increase intrajejunal pressure (from 12.42 ± 0.38 cmH2O to 13.05 ± 0.38 cmH2O, an increase of 5.07% ± 1.08%, P > 0.05), respectively. In contrast, acupuncture ST25, a homotopic acupoint, decreased not only intrajejunal pressure, but also significantly decreased frequency in normal rats and rats with constipation or diarrhea. Following demyelination of Aδ fibers, acupuncture at ST37 again augmented intrajejunal pressure to 121.48% ± 3.06% of baseline. Following capsaicin application for 24 h, acupuncture at ipsilateral ST37 increased intrajejunal pressure significantly to 106.63% ± 1.26% of basal levels when compared to measurements prior to capsaicin treatment (P < 0.05). Acupuncture at LI11, ST37, or BL25 significantly rescued methoctramine-mediated inhibition of jejunal motility amplitude from 42.83% ± 1.65% to 53.43% ± 1.95% of baseline (P < 0.05), from 45.15% ± 2.22% to 70.51% ± 2.34% of baseline (P < 0.01), and from 38.03% ± 2.34% to 70.12% ± 2.22% of baseline (P < 0.01), respectively.
CONCLUSION: Acupuncture at heterotopic acupoints increases the amplitude of jejunal motility in rats. C fibers and M2 receptors predominantly and partially mediate the regulation of jejunal motility by acupuncture, respectively.
PMCID: PMC4277964  PMID: 25561794
Acupuncture; Heterotopic acupoint; LI11; ST37; BL25; Jejunal motility; Constipation; Diarrhea; C fibers; Muscarinic receptors
7.  Predictive potential role of glutathione S-transferases polymorphisms on prognosis of breast cancer 
The aim of this study was to evaluate the clinical response to chemotherapy and treatment outcome of breast cancers patients in the presence of the GSTM1 null/present, GSTT1 null/present, and GSTP1 IIe105Val polymorphisms. Genotyping of GSTP1 rs1695, GSTT1 deletion and GSTM1 deletion was carried out on a 384-well plate format on the Sequenom MassARRAY platform. Of 382 patients, 202 patients showed good response to chemotherapy, 51 died, and 155 showed progression at the end of the study. Patients carrying GG genotype and G allele of GSTP1 rs1695 were associated with poor response to chemotherapy. In the Cox proportional hazards model, after adjusting for potential confounding factors, patients carrying GG genotype and G allele of GSTP1 rs1695 were correlated with a shorter overall survival (OS). Variants of GSTP1 rs1695 are associated with response to chemotherapy and PFS and OS of breast cancer patients, and this gene polymorphism could help in the design of individualized therapy.
PMCID: PMC4314001
Glutathione S-transferases; polymorphism; breast cancer
8.  Intracranial multiple germ cell tumors: a case report and review of literature 
Intracranial multiple germ cell tumors (GCTs) are rare. In this article, we reported a case of intracranial multiple GCTs in an 18-year-old boy with symptoms of psychosis for 8 months also. Tumors in the pineal, sellar region, corpus callosum, bilateral lateral ventricles and fourth ventricle were confirmed by enhanced magnetic resonance imaging (MRI) and stereotactic biopsy. Immunohistochemical analysis results demonstrated that the tumor cells were positive for CD117 and placental alkaline phosphatase (PLAP). The patient was treated by radiotherapy and the prescribed radiation doses were 18 Gy. After near 24 months of follow-up, no local recurrence and distant metastasis has been found.
PMCID: PMC4314009
Intracranial multiple germ cell tumors; symptoms of psychosis; pineal; sellar region; corpus callosum; lateral ventricles
9.  Changes in Responses of Neurons in Spinal and Medullary Subnucleus Reticularis Dorsalis to Acupoint Stimulation in Rats with Visceral Hyperalgesia 
The purpose of this study was to explore the mechanism of acupoints sensitization phenomenon at the spinal and medulla levels. Experiments were performed on adult male Sprague-Dawley rats and visceral noxious stimuli was generated by colorectal distension (CRD). The activities of wide dynamic range (WDR) and subnucleus reticularis dorsalis (SRD) neurons were recorded. The changes of the reactions of WDR and SRD neurons to electroacupuncture (EA) on acupoints of “Zusanli-Shangjuxu” before and after CRD stimulation were observed. The results showed that visceral nociception could facilitate the response of neurons to acupoints stimulation. In spinal dorsal horn, EA-induced activation of WDR neurons further increased to 106.84 ± 17.33% (1.5 mA) (P < 0.001) and 42.27 ± 13.10% (6 mA) (P < 0.01) compared to the neuronal responses before CRD. In medulla oblongata, EA-induced activation of SRD neurons further increased to 63.28 ± 15.96% (1.5 mA) (P < 0.001) and 25.02 ± 7.47% (6 mA) (P < 0.01) compared to that before CRD. Taken together, these data suggest that the viscerosomatic convergence-facilitation effect of WDR and SRD neurons may underlie the mechanism of acupoints sensitization. But the sensitizing effect of visceral nociception on WDR neurons is stronger than that on SRD neurons.
PMCID: PMC4262754  PMID: 25525449
10.  Aging Increases the Susceptivity of MSCs to Reactive Oxygen Species and Impairs Their Therapeutic Potency for Myocardial Infarction 
PLoS ONE  2014;9(11):e111850.
Myocardial infarction (MI) is one of the leading causes of death worldwide and Mesenchymal Stem Cells (MSCs) transplantation has been considered a promising therapy. Recently, it was reported that the therapeutic effectiveness of MSCs is dependent on the age of the donor, yet the underlying mechanism has not been thoroughly investigated. This study was designed to investigate whether this impaired therapeutic potency is caused by an increased susceptivity of MSCs from old donors to reactive oxygen species (ROS). The MSCs were isolated from the subcutaneous inguinal region of young (8–10 weeks) and old (18 months) Sprague–Dawley (SD) rats. By exposing these MSCs to H2O2, we found that the adhesion of MSCs from old donors was damaged more severely. Specifically, decreased expression of integrin and reduced phosphorylation of focal adhesion kinase Src and FAK were observed. Furthemore, H2O2 triggered an increased apoptosis of MSCs from old donors. To study the viability and therapeutic potency of MSCs from young and old donors in vivo, these MSCs were transplanted into acute MI model rats. We observed a more rapidly decreased survival rate of the old MSCs in the infarct region, which may be caused by their increased susceptivity to the micro-environmental ROS, as transplantation of the old MSCs with N-acetyl-L-cysteine (NAC), a ROS scavenger, protected them. The low viability of engrafted old MSCs consequently impaired their therapeutic effectiveness, judging by the histology and function of heart. Our study may help to understand the mechanism of MSCs-host interaction during MI, as well as shed light on the design of therapeutic strategy in clinic.
PMCID: PMC4230939  PMID: 25393016
11.  Efficient p-type dye-sensitized solar cells with all-nano-electrodes: NiCo2S4 mesoporous nanosheet counter electrodes directly converted from NiCo2O4 photocathodes 
Nanoscale Research Letters  2014;9(1):608.
We report the successful growth of NiCo2S4 nanosheet films converted from NiCo2O4 nanosheet films on fluorine-doped tin oxide substrates by a low-temperature solution process. Low-cost NiCo2S4 and NiCo2O4 nanosheet films were directly used for replacing conventional Pt and NiO as counter electrodes and photocathodes, respectively, to construct all-nano p-type dye-sensitized solar cells (p-DSSCs) with high performance. Compared to Pt, NiCo2S4 showed higher catalytic activity towards the I-/I3- redox in electrolyte, resulting in an improved photocurrent density up to 2.989 mA/cm2, which is the highest value in reported p-DSSCs. Present p-DSSCs demonstrated a cell efficiency of 0.248 % that is also comparable with typical NiO-based p-DSSCs.
PMCID: PMC4257056  PMID: 25489277
Dye-sensitized solar cells; p-type; Counter electrodes; Nanosheets; Ternary sulfides
12.  Development of aminoglycoside and β-lactamase resistance among intestinal microbiota of swine treated with lincomycin, chlortetracycline, and amoxicillin 
Lincomycin, chlortetracycline, and amoxicillin are commonly used antimicrobials for growth promotion and infectious disease prophylaxis in swine production. In this study, we investigated the shifts and resistance development among intestinal microbiota in pregnant sows before and after lincomycin, chlortetracycline, and amoxicillin treatment by using phylogenetic analysis, bacterial enumeration, and PCR. After the antimicrobial treatment, shifts in microbial community, an increased proportion of resistant bacteria, and genes related to antimicrobial resistance as compared to the day before antimicrobial administration (day 0) were observed. Importantly, a positive correlation between antimicrobial resistance gene expression in different categories, especially those encoding aminoglycoside and β-lactamase and antimicrobial resistance, was observed. These findings demonstrate an important role of antimicrobial usage in animals in the development of antimicrobial resistance, and support the notion that prudent use of antimicrobials in swine is needed to reduce the risk of the emergence of multi-drug resistant zoonotic pathogens.
PMCID: PMC4219486  PMID: 25408688
culture-independent method; qPCR; antimicrobial-resistant genes; 16S rRNA; Bacterial Enumeration
13.  Effect of supersaturation on hillock of directional Growth of KDP crystals 
Scientific Reports  2014;4:6886.
KDP single crystals were grown in aqueous solution by using “point seeds” with a defined crystallographic direction of 59° to the Z axis. When hillock slopes on the (100) face of KDP crystals were measured within the supersaturation (σ) range of 0 < σ ≤ 0.06, the slope of hillocks with hollow cores depended nonlinearly on supersaturation. Below σ = 0.02, the hillock slope depended on supersaturation, but when σ was ≥ 0.02, the hillock slope increased more gradually and was less dependent on supersaturation. Hollow funnel-shaped growth dislocation on the (100) face of KDP crystals was observed at σ = 0.04, characterized by large holes with micro-steps and step bunching inside, the formation of which were analyzed. The result verified that the reversed growth appears to occur within hollow channels found on growth hillocks.
PMCID: PMC4217111  PMID: 25363505
14.  Survey of Tuberculosis Hospitals in China: Current Status and Challenges 
PLoS ONE  2014;9(11):e111945.
Hospitals will play an increasingly important role in delivering TB services in China, however little is known in terms of the current landscape of the hospital system that delivers TB care.
Methodology/Principal Findings
In order to examine the status of TB hospitals we performed a study in which a total of 203 TB hospitals, with 30 beds or more, were enrolled from 31 provinces and Xinjiang Production and Construction Corps. Of the 203 hospitals, 93 (45.8%) were located in the eastern region of China, 84 (41.4%) in the central region, and 26 (12.8%) in the western region, while there were 34.6 million TB patients in western China, accounting for 34.6% of the TB burden nationwide. The total number of staff in these 203 hospitals was 83,011, of which 18,899 (22.8%) provided health services for TB patients, (physicians, nurses, lab technicians, etc). Although both the overall number of the health care workers and TB staff in the 203 hospitals increased from the year 1999 to 2009, the former increased by 52%, while the latter increased only by 34%, showing that the percentage of TB staff declined significantly (χ2 = 181.7, P<0.01). The total annual income of the 203 hospitals increased 5.5 fold from 1999 to 2009, while that from TB care increased 3.8 fold during the same period. TB care and control experienced a relatively slower development during this period as shown by the lower percentage of TB staff and the lesser increase in income from TB care in the hospitals.
In conclusion, our findings demonstrated that hospital resources are scarcer in western China as compared with eastern China. In view of the current findings, policymakers are urged to address the uneven distribution of medical resources between the underdeveloped west and the more affluent eastern provinces.
PMCID: PMC4218826  PMID: 25365259
15.  Three-layer reconstruction of large urethrocutaneous fistulas using scrotal-septal flaps 
Canadian Urological Association Journal  2014;8(11-12):E828-E831.
The repair of large urethrocutaneous fistulas (UCFs) commonly involves reconstruction of the urethra, waterproof layer and skin coverage, which deploy different tissues from different flaps. To simplify the multiple procedures, we explored to use one flap (a scrotal-septal flap) to reconstruct three layers in UCF repairing in one stage.
Between January 2011 and July 2012, 29 patients with large UCFs (ranging from 1.0 to 2.0 cm) were treated using scrotal-septal flaps for three-layer reconstruction. Every patient has an unbroken scrotum. The hair follicles in the donor site were destroyed using a radiosurgical knife 2 months before the operation. The flap was divided into three zones, which were flipped, folded, and extended respectively to form the urethra, waterproof layer and skin coverage.
The patients were followed up between 6 to 12 months. No fistula recurrence was observed. All flaps survived, except in one case, in which the distal skin flap was lost but stenosis or fistula did not develop. Two patients underwent second operations to refine the aesthetic results.
The scrotal-septal flap can be transferred in an overturning-folding-advancement fashion and can simultaneously involve the reconstruction of the urethra, waterproof barrier and skin coverage. This is a simple and reliable alternative for large UCFs (≤2 cm) repairing at the penoscrotal junction; however, it cannot be used in patients with a damaged scrotal septum.
PMCID: PMC4250248  PMID: 25485011
16.  Evaluation of Osseointegration around Tibial Implants in Rats by Ibandronate-Treated Nanotubular Ti-32Nb-5Zr Alloy 
Biomolecules & Therapeutics  2014;22(6):563-569.
Materials with differing surfaces have been developed for clinical implant therapy in dentistry and orthopedics. This study was designed to evaluate bone response to titanium alloy containing Ti-32Nb-5Zr with nanostructure, anodic oxidation, heat treatment, and ibandronate coating. Rats were randomly assigned to two groups for implantation of titanium alloy (untreated) as the control group and titanium alloy group coated with ibandronate as the experimental group. Then, the implants were inserted in both tibiae of the rats for four weeks. After implantation, bone implant interface, trabecular microstructure, mechanical fixation was evaluated by histology, micro-computed tomography (μCT) and the push-out test, respectively. We found that the anodized, heat-treated and ibandronate-coated titanium alloy triggered pronounced bone implant integration and early bone formation. Ibandronate-coated implants showed elevated values for removal torque and a higher level of BV/TV, trabecular thickness and separation upon analysis with μCT and mechanical testing. Similarly, higher bone contact and a larger percentage bone area were observed via histology compared to untreated alloy. Furthermore, well coating of ibandronate with alloy was observed by vitro releasing experiment. Our study provided evidences that the coating of bisphosphonate onto the anodized and heat-treated nanostructure of titanium alloy had a positive effect on implant fixation.
PMCID: PMC4256038  PMID: 25489426
Dental implants; Osseointegration; Titanium alloy; Ibandronate; Nanotubes
17.  Overexpression of MicroRNA-30b Improves Adenovirus-Mediated p53 Cancer Gene Therapy for Laryngeal Carcinoma 
MicroRNAs play important roles in laryngeal carcinoma and other cancers. However, the expression of microRNAs in paracancerous tissue has been studied less. Here, using laser capture microdissection (LCM), we detected the expression of microRNAs in paracancerous tissues. Among all down-regulated microRNAs in the center area of tumor tissues, only miR-30b expression was significantly reduced in paracancerous tissues compared to surgical margins. Therefore, to further investigate the effect of miR-30b on laryngeal carcinoma, we stably overexpressed miR-30b in laryngeal carcinoma cell line HEp-2 cells. It was found that although there was no significant difference in cell viability between miR-30b overexpressed cells and control HEp-2 cells, p53 expression was obviously enhanced in miR-30b overexpressed cells. Whether miR-30b could improve the anti-tumor effect of adenovirus-p53 (Ad-p53) in laryngeal carcinoma and other cancer cell lines was also evaluated. It was found that in miR-30b overexpressed HEp-2 cells, p53-mediated tumor cell apoptosis was obviously increased both in vitro and in vivo. MDM2-p53 interaction might be involved in miR-30b-mediated anti-tumor effect. Together, results suggested that miR-30b could modulate p53 pathway and enhance p53 gene therapy-induced apoptosis in laryngeal carcinoma, which could provide a novel microRNA target in tumor therapy.
PMCID: PMC4264135  PMID: 25356506
laryngeal carcinoma; miR-30b; p53; field cancerization
18.  Absence of Gamma-Interferon-Inducible Lysosomal Thiol Reductase (GILT) Is Associated with Poor Disease-Free Survival in Breast Cancer Patients 
PLoS ONE  2014;9(10):e109449.
Tumor immunosurveillance is known to be of critical importance in controlling tumorigenesis and progression in various cancers. The role of gamma-interferon-inducible lysosomal thiol reductase (GILT) in tumor immunosurveillance has recently been studied in several malignant diseases, but its role in breast cancer remains to be elucidated. In the present study, we found GILT as a significant different expressed gene by cDNA microarray analysis. To further determine the role of GILT in breast cancer, we examined GILT expression in breast cancers as well as noncancerous breast tissues by immunohistochemistry and real-time PCR, and assessed its association with clinicopathologic characteristics and patient outcome. The absence of GILT expression increased significantly from 2.02% (2/99) in noncancerous breast tissues to 15.6% (34/218) in breast cancer tissues (P<0.001). In accordance with its proliferation inhibiting function, GILT expression was inversely correlated with Ki67 index (P<0.05). In addition, absence of GILT was positively correlated with adverse characteristics of breast cancers, such as histological type, tumor size, lymph nodes status, and pTNM stage (P<0.05). Consistently, breast cancers with reduced GILT expression had poorer disease-free survival (P<0.005). Moreover, significantly decreased expression of GILT was found in both primary and metastatic breast cancer cells, in contrast to normal epithelial cells. These findings indicate that GILT may act as a tumor suppressor in breast cancer, in line with its previously suggested role in anti-tumor immunity. Thus, GILT has the potential to be a novel independent prognostic factor in breast cancer and further studies are needed to illustrate the underlying mechanism of this relationship.
PMCID: PMC4204821  PMID: 25333930
19.  Concomitant Inactivation of Foxo3a and Fancc or Fancd2 Reveals a Two-Tier Protection from Oxidative Stress-Induced Hydrocephalus 
Antioxidants & Redox Signaling  2014;21(12):1675-1692.
Aims: This study seeks at investigating the cause of hydrocephalus, and at identifying therapeutic targets for the prevention of hydrocephalus. Results: In this study, we show that inactivation of the Foxo3a gene in two mouse models of Fanconi anemia (FA) leads to the development of hydrocephalus in late embryonic stage and after birth. More than 50% of Foxo3a−/− Fancc−/− or Foxo3a−/− Fancd2−/− mice die during embryonic development or within 6 months of life as a result of hydrocephalus characterized by cranial distortion, dilation of the ventricular system, reduced thickness of the cerebral cortex, and disorganization of the ependymal cilia and subcommissural organ. Combined deficiency of Foxo3a and Fancc or Fancd2 not only impairs the self-renewal capacity but also markedly increases the apoptosis of neural stem and progenitor cells (NSPCs), leading to defective neurogenesis. Increased accumulation of reactive oxygen species (ROS) and subsequently de-regulated mitosis and ultimately apoptosis in the neural stem or progenitor cells is identified as one of the potential mechanisms of congenital obstructive hydrocephalus. Innovation: The work unravels a two-tier protective mechanism for preventing oxidative stress-induced hydrocephalus. Conclusion: The deletion of Foxo3a in FA mice increased the accumulation of ROS and subsequently de-regulated mitosis and ultimately apoptosis in the NSPCs, leading to hydrocephalus development. Antioxid. Redox Signal. 21, 1675–1692.
PMCID: PMC4186827  PMID: 24483844
20.  Profiling of alternative polyadenylation sites in luminal B breast cancer using the SAPAS method 
Breast cancer (BC) is a leading cause of cancer-related mortality in females and is recognized as a molecularly heterogeneous disease. Previous studies have suggested that alternative messenger RNA (mRNA) processing, particularly alternative polyadenylation [poly(A)] (APA), can be a powerful molecular biomarker with prognostic potential. Therefore, in the present study, we profiled APA sites in the luminal B subtype of BC by sequencing APA sites (SAPAS) method, in order to assess the relation of these APA site-switching events to the recognized molecular subtypes of BC, and to discover novel candidate genes and pathways in BC. Through comprehensive analysis, the trend of APA site-switching events in the 3′ untranslated regions (3′UTRs) in the luminal B subtype of BC were found to be the same as that in MCF7 cell lines. Among the genes involved in the events, a significantly greater number of genes was found with shortened 3′UTRs in the samples, which were samples of primary cancer with relatively low proliferation. These findings may provide novel information for the clinical diagnosis and prognosis on a molecular level. Several potential biomarkers with significantly differential tandem 3′UTRs and expression were found and validated. The related biological progresses and pathways involved were partly confirmed by other studies. In conclusion, this study provides new insight into the diagnosis and prognosis of BC from the APA site profile aspect.
PMCID: PMC4249744  PMID: 25333330
profile of alternative adenylation sites; breast cancer; tandem 3′ untranslated region; subtypes in breast cancer; sequencing alternative polyadenylation sites
21.  Visualization-Aided Classification Ensembles Discriminate Lung Adenocarcinoma and Squamous Cell Carcinoma Samples Using Their Gene Expression Profiles 
PLoS ONE  2014;9(10):e110052.
The widespread application of microarray experiments to cancer research is astounding including lung cancer, one of the most common fatal human tumors. Among non-small cell lung carcinoma (NSCLC), there are two major histological types of NSCLC, adenocarcinoma (AC) and squamous cell carcinoma (SCC).
In this paper, we proposed to integrate a visualization method called Radial Coordinate Visualization (Radviz) with a suitable classifier, aiming at discriminating two NSCLC subtypes using patients' gene expression profiles. Our analyses on simulated data and a real microarray dataset show that combining with a classification method, Radviz may play a role in selecting relevant features and ameliorating parsimony, while the final model suffers no or least loss of accuracy. Most importantly, a graphic representation is more easily understandable and implementable for a clinician than statistical methods and/or mathematic equations.
To conclude, using the NSCLC microarray data presented here as a benchmark, the comprehensive understanding of the underlying mechanism associated with NSCLC and of the mechanisms with its subtypes and respective stages will become reality in the near future.
PMCID: PMC4198193  PMID: 25335090
22.  Chemical Analog-to-Digital Signal Conversion Based on Robust Threshold Chemistry and Its Evaluation in the Context of Microfluidics-Based Quantitative Assays 
Journal of the American Chemical Society  2013;135(39):10.1021/ja4062882.
In this paper, we describe a nonlinear threshold chemistry based on enzymatic inhibition and demonstrate how it can be coupled with microfluidics to convert a chemical concentration (analog input) into patterns of ON or OFF reaction outcomes (chemical digital readout). Quantification of small changes in concentration is needed in a number of assays, such as that for cystatin C, where a 1.5-fold increase in concentration may indicate the presence of acute kidney injury or the progression of chronic kidney disease. We developed an analog-to-digital chemical signal conversion that gives visual readout and applied it to an assay for cystatin C as a model target. The threshold chemistry is based on enzymatic inhibition and gives sharper responses with tighter inhibition. The chemistry described here uses acetylcholinesterase (AChE) and produces an unambiguous color change when the input is above a pre-determined threshold concentration. An input gives a pattern of ON/OFF responses when subjected to a monotonic sequence of threshold concentrations, revealing the input concentration at the point of transition from OFF to ON outcomes. We demonstrated that this threshold chemistry can detect a 1.30–fold increase in concentration at 22 °C, and that it is robust to experimental fluctuations: it provided the same output despite changes in temperature (22–34 °C) and readout time (10-fold range). We applied this threshold chemistry to diagnostics by coupling it with a traditional sandwich immunoassay for serum cystatin C. Because one quantitative measurement comprises several assays, each with its own threshold concentration, we used a microfluidic SlipChip device to process 12 assays in parallel, detecting a 1.5-fold increase (0.64 mg/L (49 nM) to 0.96 mg/L (74 nM)) of cystatin C in serum. We also demonstrated applicability to analysis of patient serum samples and the ability to image results using a cell phone camera. This work indicates that combining developments in nonlinear chemistries with microfluidics may lead to the development of user-friendly diagnostic assays with simple readouts.
PMCID: PMC3860884  PMID: 24060606
23.  Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth 
Cell Research  2014;24(10):1164-1180.
An increased population of CD4+CD25highFoxp3+ regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. However, the underlying mechanism remains unclear. Here we observed an increased secretion of miR-214 in various types of human cancers and mouse tumor models. Tumor-secreted miR-214 was sufficiently delivered into recipient T cells by microvesicles (MVs). In targeted mouse peripheral CD4+ T cells, tumor-derived miR-214 efficiently downregulated phosphatase and tensin homolog (PTEN) and promoted Treg expansion. The miR-214-induced Tregs secreted higher levels of IL-10 and promoted tumor growth in nude mice. Furthermore, in vivo studies indicated that Treg expansion mediated by cancer cell-secreted miR-214 resulted in enhanced immune suppression and tumor implantation/growth in mice. The MV delivery of anti-miR-214 antisense oligonucleotides (ASOs) into mice implanted with tumors blocked Treg expansion and tumor growth. Our study reveals a novel mechanism through which cancer cell actively manipulates immune response via promoting Treg expansion.
PMCID: PMC4185347  PMID: 25223704
secreted microRNA; regulatory T cell; PTEN; microvesicle; immune evasion; tumor
24.  Recombinase Polymerase Amplification (RPA) of CaMV-35S Promoter and nos Terminator for Rapid Detection of Genetically Modified Crops 
Recombinase polymerase amplification (RPA) is a novel isothermal DNA amplification and detection technology that enables the amplification of DNA within 30 min at a constant temperature of 37–42 °C by simulating in vivo DNA recombination. In this study, based on the regulatory sequence of the cauliflower mosaic virus 35S (CaMV-35S) promoter and the Agrobacterium tumefaciens nopaline synthase gene (nos) terminator, which are widely incorporated in genetically modified (GM) crops, we designed two sets of RPA primers and established a real-time RPA detection method for GM crop screening and detection. This method could reliably detect as few as 100 copies of the target molecule in a sample within 15–25 min. Furthermore, the real-time RPA detection method was successfully used to amplify and detect DNA from samples of four major GM crops (maize, rice, cotton, and soybean). With this novel amplification method, the test time was significantly shortened and the reaction process was simplified; thus, this method represents an effective approach to the rapid detection of GM crops.
PMCID: PMC4227211  PMID: 25310647
recombinase polymerase amplification (RPA); isothermal amplification; CaMV-35S promoter (P-35S); nos terminator (T-nos); genetically modified crops (GMCs)
25.  Breast cancer awareness among women in Eastern China: a cross-sectional study 
BMC Public Health  2014;14(1):1004.
High breast cancer mortality has been attributed to lack of public awareness, which leads to late diagnoses. As little is known about the level of knowledge and awareness of breast cancer in China, this study was designed to explore it among women in Eastern China.
We conducted a cross-sectional survey covering 122,058 females around Shandong, Hebei, Jiangsu and Tianjin, in Eastern China, using in-person interviews based on a self-designed structured questionnaire. Student’s t-test, Pearson’s χ2 test, reliability analysis, exploratory factor analysis, univariate and multivariate logistic regression analyses were performed in the statistical analysis.
The results showed poor awareness of breast cancer among women aged 25–70 years in Eastern China. Only 18.6% of women were highly aware in the study, whereas 81.4% were poorly aware. Among all participants, family history of breast cancer was the best accepted risk factor for breast cancer (awareness rate 31.5%), followed by menarche at age before 12 (11.2%), no parity or late childbirth (13.9%), menopause at a late age (13.7%), high-fat diets (19.1%), long time drinking (19.5%) and long-term use of estrogen drugs (20.7%). Multivariate logistic regression analysis (α = 0.05) identified nine variables that predicted awareness of breast cancer: age (OR = 0.975, 95% CI: 0.960–0.990), location (OR = 1.675, 95% CI: 1.602–1.752), occupation (OR = 4.774, 95% CI: 4.316–5.281), family history of breast cancer (OR = 1.234, 95% CI: 1.073–1.420), household annual income (OR = 0.418, 95% CI: 0.400–0.436), behavioral prevention score (OR = 4.137, 95% CI: 3.991–4.290), no smoking (OR = 2.113, 95% CI: 1.488–2.999), no drinking (OR = 1.427, 95% CI: 1.018–2.000), overall life satisfaction (OR = 0.707, 95% CI: 0.683–0.731).
Our study indicates insufficient awareness of breast cancer among women in Eastern China, and an urgent need for health education programs on this subject.
PMCID: PMC4180963  PMID: 25257142
Breast cancer; Knowledge; Chinese women; Cancer awareness

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